Over the last decade tremendous progress has been made in identifying therapeutic targets for Duchenne muscular dystrophy (DMD), a devastating progressive neuromuscular disease. However the design of clinical trials has been challenging, with sparse natural history data, a limited patient pool to recruit from, and few sensitive noninvasive outcome measures. Recent setbacks in several clinical trials have underscored the crucial need for transitional outcome measures that are sensitive across various stages of disease progression, including in non-ambulatory boys, and can reliably be implemented at multiple sites. In the initial funding cycle of this grant, we successfully implemented the first multicenter MR study in DMD and demonstrated that lower extremity quantitative MR measures (e.g. MRS fat fraction and MRI/MRS T2) are sensitive to disease progression in ambulatory boys, responsive to corticosteroid treatment, and reliable across multiple sites. In Aim 1 of this renewal application, we propose to extend the natural history MR biomarker study (iDMD) in the lower extremity muscles. Given the age distribution of the iDMD subject cohort (n=136; ages 7-18 years) we have an unprecedented opportunity to examine the sensitivity of quantitative MR measures (including 8-point Dixon and UTE) at different stages of disease progression, assess their value in predicting loss of ambulation, and obtain extremely valuable long term natural history data. In Aim 2, we will develop and validate upper extremity MR biomarkers and outcome measures in the same subject cohort. Specifically, we will perform a detailed MRI/MRS characterization of the forearm, upper arm and shoulder girdle. No prior MR imaging studies in DMD have been performed on upper extremity muscles that are essential for function, such as the biceps and deltoid, leaving a considerable gap in knowledge. MR measures in boys with DMD will be repeated at yearly intervals. In addition, we will correlate changes in MRI/MRS measures with loss in upper extremity function and strength. Finally, in Aim 3 we will build on our current infrastructure to establish a National Tissue and Data Resource, linking biological samples (fibroblasts, blood/urine) with genetic, detailed MRI/MRS, strength, functional, and demographic data collected in iDMD and making them available to the larger DMD community. This project addresses several critical barriers in therapeutic development and has the potential to significantly improve future clinical trials in DMD, as well as other neuromuscular diseases.